Brain Substrates of Affect Dysregulation in Cocaine Addiction: A Pilot Study NIDA PAR-09-073 R03 Imaging-Science Track Award for Research Transition (I/START) Affect dysregulation is pervasive in alcohol and drug addiction, and is a recognized risk factor for relapse in cocaine addiction. For cocaine-dependent patients, their difficulties in modulating emotions may be due to the documented structural and functional deficits in the prefrontal cortical brain regions (PFC) responsible for regulating limbic structures involved in emotional arousal. Our preliminary data reveals attenuated functional connection between the PFC and the amygdala in cocaine-dependent patients who were exposed to emotionally evocative stimuli. At this time, however, no studies have characterized the brain activity in cocaine-dependent patients while actually attempting to regulate their emotions. The objective of the current proposal is to demonstrate the utility of an affect regulation paradigm to examine the neural mechanisms of affect regulation. We will administer the paradigm to 25 cocaine-dependent patients who are participating in three ongoing NIDA-funded neuroimaging protocols. Twenty-five non-addicted controls will be recruited to obtain comparison neuroimaging data. In line with the purpose of I/START, the imaging results will be used as pilot data for the P.I.'s first independently-funded research: An investigation of the link between neural substrates of affect dysregulation and vulnerability to drug relapse. Our ultimate goals are to identify the neuroanatomical circuits involved in affect dysregulation and to use the anomalies as a predictor of relapse and treatment response in cocaine addiction. Specific Aims: Using the affect regulation paradigm, we aim: 1) To characterize the brain substrates associated with affect regulation within cocaine and non-addicted control groups, with an hypothesis that regulatory attempts will recruit the PFC system (i.e., increase in PFC activation) in both groups;and 2) To compare the PFC-limbic connectivity associated with affect regulation between cocaine patients and controls. We hypothesize that the control group will show greater functional connectivity than the cocaine patients. Relevance and Significance: Using this well-characterized paradigm in our clinical sample is a novel approach to examine the role of affect dysregulation in addiction. The proposed research will have wide clinical relevance given the prevalence of affect dysregulation in various addiction disorders (e.g., cocaine dependence, eating disorder, gambling) and comorbid psychiatric conditions (e.g., depression, anxiety). Further, it will provide significant insights into the neural mechanisms of affect dysregulation in these clinical disorders, as well as critical treatment targets for behavioral and pharmacological interventions. PUBLIC HEALTH RELEVANCE: The proposed pilot project will examine the neural mechanisms of affect regulation using cognitive strategies. In line with the purpose of the I/START, the pilot imaging results will be used to develop a more extensive research proposal, to investigate the link between neural substrates of affect dysregulation and vulnerability to drug relapse. The proposed research has relevance to public health because the findings will provide critical insights into the neural mechanisms of affect dysregulation in substance addiction, and will provide direct treatment targets for behavioral and pharmacological interventions.